Details of the Drug Combination

General Information of Drug Combination (ID: DCJMZRD)

• Drug Combination Name: Benazepril + Candesartan
• Indication: Hypertension; Status: Phase 1 [1]
• Component Drugs:
  Benazepril (DMH1M9B): Small molecular drug
  Candesartan (DMRK8OT): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Benazepril

Disease Entry	ICD 11	Status	REF
Hypertension	BA00-BA04	Approved	[2]
Malignant essential hypertension	BA00	Approved	[3]

Benazepril Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Angiotensin-converting enzyme (ACE)	TTL69WB	ACE_HUMAN	Inhibitor	[6]

Benazepril Interacts with 2 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Peptide transporter 1 (SLC15A1)	DT9G7XN	S15A1_HUMAN	Substrate	[7]
Peptide transporter 2 (SLC15A2)	DT8QKNP	S15A2_HUMAN	Substrate	[7]

Benazepril Interacts with 1 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Methylenetetrahydrofolate reductase (MTHFR)	DEOXTPZ	MTHR_HUMAN	Metabolism	[8]

Benazepril Interacts with 5 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Renin (REN)	OT52GZR2	RENI_HUMAN	Increases Expression	[9]
Transforming growth factor beta-1 proprotein (TGFB1)	OTV5XHVH	TGFB1_HUMAN	Decreases Expression	[10]
Protein AMBP (AMBP)	OTLU8GU8	AMBP_HUMAN	Decreases Expression	[11]
Lysosomal Pro-X carboxypeptidase (PRCP)	OTIUY91L	PCP_HUMAN	Affects Response To Substance	[12]
Beta-2 adrenergic receptor (ADRB2)	OTSDOX4Q	ADRB2_HUMAN	Affects Response To Substance	[13]

Indication(s) of Candesartan

Disease Entry	ICD 11	Status	REF
Chronic heart failure	BD1Z	Approved	[4]
Hypertension	BA00-BA04	Approved	[5]
Malignant essential hypertension	BA00	Approved	[4]

Candesartan Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Angiotensin II receptor type-1 (AGTR1)	TT8DBY3	AGTR1_HUMAN	Antagonist	[15]

Candesartan Interacts with 5 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
UDP-glucuronosyltransferase 1A1 (UGT1A1)	DEYGVN4	UD11_HUMAN	Metabolism	[16]
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[17]
UDP-glucuronosyltransferase 1A3 (UGT1A3)	DEF2WXN	UD13_HUMAN	Metabolism	[18]
Carboxylesterase 1 (CES1)	DEB30C5	EST1_HUMAN	Metabolism	[19]
Prostaglandin G/H synthase 1 (COX-1)	DE073H6	PGH1_HUMAN	Metabolism	[18]

Candesartan Interacts with 5 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Renin (REN)	OT52GZR2	RENI_HUMAN	Decreases Activity	[20]
C-reactive protein (CRP)	OT0RFT8F	CRP_HUMAN	Decreases Expression	[21]
Interleukin-8 (CXCL8)	OTS7T5VH	IL8_HUMAN	Decreases Expression	[14]
Cytochrome b-245 light chain (CYBA)	OT16N9ZO	CY24A_HUMAN	Decreases Expression	[22]
CD40 ligand (CD40LG)	OT75Z6A6	CD40L_HUMAN	Decreases Expression	[23]

References

• [1] ClinicalTrials.gov (NCT04467931) ACEI or ARB and COVID-19 Severity and Mortality in US Veterans
• [2] URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 6374).
• [3] Amlodipine FDA Label
• [4] Candesartan FDA Label
• [5] URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 587).
• [6] Efficacy of benazepril hydrochloride to delay the progression of occult dilated cardiomyopathy in Doberman Pinschers. J Vet Intern Med. 2009 Sep-Oct;23(5):977-83.
• [7] Transport of angiotensin-converting enzyme inhibitors by H+/peptide transporters revisited. J Pharmacol Exp Ther. 2008 Nov;327(2):432-41.
• [8] Effects of MTHFR and MS gene polymorphisms on baseline blood pressure and Benazepril effectiveness in Chinese hypertensive patients. J Hum Hypertens. 2011 Mar;25(3):172-7.
• [9] Sympathomoderating influence of benazepril in essential hypertension. J Hypertens. 1992 Apr;10(4):373-8. doi: 10.1097/00004872-199204000-00009.
• [10] Transforming growth factor-beta1 is associated with kidney damage in patients with essential hypertension: renoprotective effect of ACE inhibitor and/or angiotensin II receptor blocker. Nephrol Dial Transplant. 2008 Sep;23(9):2841-6. doi: 10.1093/ndt/gfn159. Epub 2008 Apr 5.
• [11] Low-dose dual blockade of the renin-angiotensin system improves tubular status in non-diabetic proteinuric patients. Scand J Urol Nephrol. 2005;39(6):511-7. doi: 10.1080/00365590510031264.
• [12] E112D polymorphism in the prolylcarboxypeptidase gene is associated with blood pressure response to benazepril in Chinese hypertensive patients. Chin Med J (Engl). 2009 Oct 20;122(20):2461-5.
• [13] Beta2 adrenergic receptor gene Arg16Gly polymorphism is associated with therapeutic efficacy of benazepril on essential hypertension in Chinese. Clin Exp Hypertens. 2004 Aug;26(6):581-92. doi: 10.1081/ceh-200031839.
• [14] Angiotensin II type 1 receptor antagonist candesartan as an angiogenic inhibitor in a xenograft model of bladder cancer. Clin Cancer Res. 2006 May 1;12(9):2888-93. doi: 10.1158/1078-0432.CCR-05-2213.
• [15] Candesartan: widening indications for this angiotensin II receptor blocker Expert Opin Pharmacother. 2009 Aug;10(12):1995-2007.
• [16] The human UDP-glucuronosyltransferase UGT1A3 is highly selective towards N2 in the tetrazole ring of losartan, candesartan, and zolarsartan. Biochem Pharmacol. 2008 Sep 15;76(6):763-72.
• [17] Product Monograph of Atacand.
• [18] Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675.
• [19] Different hydrolases involved in bioactivation of prodrug-type angiotensin receptor blockers: carboxymethylenebutenolidase and carboxylesterase 1. Drug Metab Dispos. 2013 Nov;41(11):1888-95.
• [20] A nonpeptide, piperidine renin inhibitor provides renal and cardiac protection in double-transgenic mice expressing human renin and angiotensinogen genes. Cardiovasc Drugs Ther. 2008 Dec;22(6):469-78. doi: 10.1007/s10557-008-6131-x. Epub 2008 Aug 5.
• [21] Candesartan reduces oxidative stress and inflammation in patients with essential hypertension. Hypertens Res. 2003 Sep;26(9):691-7. doi: 10.1291/hypres.26.691.
• [22] Protective mechanisms of the angiotensin II type 1 receptor blocker candesartan against cerebral ischemia: in-vivo and in-vitro studies. J Hypertens. 2008 Jul;26(7):1435-45. doi: 10.1097/HJH.0b013e3283013b6e.
• [23] Additive beneficial effects of fenofibrate combined with candesartan in the treatment of hypertriglyceridemic hypertensive patients. Diabetes Care. 2006 Feb;29(2):195-201. doi: 10.2337/diacare.29.02.06.dc05-1418.